Trauma is the most common cause of death below age 45 and leads to enormous health care costs and lost productivity. We do not really understand why injury causes critical illness, ie why a local mechanical event such as tissue crushing a limb leads to lung inflammation and failure. We do know that injury can cause inflammation that such inflammation is clinically indistinguishable from that caused by infection. We know that infections cause inflammation because some of the molecules on the surface of bacteria are recognized by our immune system. What we recognized was that some of our intra-cellular machinery is evolutionary derived from bacteria. Thus we reasoned that if cells were destroyed by trauma some of the intra-cellular contents that leaked out might look to our immune system like evidence of infection. In our ground-breaking preliminary work, we have now shown conclusively that debris from intracellular structures called mitochondria is released into the circulation in clinical trauma. Our preliminary work showed this debris has important functional effects on inflammation and immunity and that mitochondrial debris is a potent 'missing link'between trauma and inflammation. The two major components of mitochondrial debris we have examined so far are mitochondrial proteins and mitochondrial DNA. Both potently activate immune cells. So we believe that tissue destruction causes inflammation when dead or injured cells release mitochondrial debris that looks like bacteria to the immune system. Thus the debris causes inflammatory responses that look like infection. If we understand this process we should be able to intervene in it. So we propose to study the pathways by which mitochondrial debris activates immunity after trauma. We will study 1) the role of mitochondrial proteins in immunity, 2) the role of mitochondrial DNA in immunity and 3) how exposure to these two 'damage'molecules interacts to cause organ injury. PUBLIC HEALTH RELEVANCE: The primary causes of inflammation after injury are unknown. Intracellular contents however, can activate immune responses by exposing molecules that are normally hidden within cells. Mitochondria are intracellular structures that were once free-living bacteria, So they contain molecular motifs that can look like bacteria to the human immune system. In trauma cells are destroyed. We found this process releases molecular motifs, simulates infection and causes immune responses that make patients ill. We will study this phenomenon in order to improve the care and outcomes of trauma victims.